This project responds to Notice NOT-OD-09-058, Enabling RPGs to Leverage NCRR Center and Center-like Programs. Plasmacytoid dendritic cells (PDC) represent a unique secretory cell type that plays a critical role in innate immune responses. During viral infections, PDC secrete massive amounts of type I interferon (IFN), prime anti-viral T cell responses, and activate multiple immune cell types. In addition to infectious immunity, PDC are implicated in many immunological phenomena including anti-tumor immunity, allergy/asthma and autoimmunity. The PDC possess unique features and gene expression patterns that facilitate their direct recognition of viruses and high level IFN secretions. However the molecular mechanisms that regulate lineage commitment, maturation, and function of PDC remain poorly understood. The overall goal of our research is to dissect the regulation of PDC development and function at the molecular level. Our work on the parent grant has indentified E protein E2-2 as a key transcriptional regulator of PDC development in mice and humans. We also found the E2-2 directly activated transcriptional factors and receptors critical for pDC function and identified novel E2-2 targets in PDC development and function. In collaboration with the NCRR Program, the Knockout Mouse Project (KOMP), we will generate and analyze loss-of-function mouse mutant strains for several PDC-enriched genes regulate by E2-2. These studies would help elucidate the molecular basis of PDC development and function and thus pave the way for immunotherapeutic approaches directed at the PDC. PUBLIC HEALTH REVELANCE: The study is aimed at molecular and genetic analysis of plasmacytoid dendritic cells (PDC), a unique immune cell type that plays a major role in anti-viral immune responses and in autoimmunity. The elucidation of molecular mechanisms that govern PDC development and function would pave the way for novel therapeutic approaches targeting PDC function in infections and autoimmune diseases.